27. Drugs that increase regional blood flow. Drug treatment of obesity

From greek.doctor

Introduction to drugs used to enhance regional blood flow

These drugs are used to enhance perfusion of organs, either because they require more perfusion or because their perfusion has been compromised by vasospasm or atherosclerosis. More precisely, these drugs are useful in peripheral artery disease-induced intermittent claudication, erectile dysfunction and Raynaud phenomenon.

In cases where one artery is blocked by atherosclerotic regions, giving drugs to enhance the blood flow may cause blood to be routed to other arteries. Blood will then be “stolen” from the ischaemic region supplied by the atherosclerotic artery. This is called steal syndrome.

Many of these drugs enhance microcirculation by increasing the deformability of RBCs, inhibiting platelet aggregation or enhancing fibrinolysis.

Dihydropyridines

Dihydropyridines like nifedipine and nimodipine.

Indications

Can be used to treat vasospasm after a subarachnoid haemorrhage, to increase blood flow to ischaemic brain tissue. They’re also the first-line choice for treating Raynaud phenomenon.

Mechanism of action

Block calcium channels, preventing influx of calcium ions into smooth muscles of vessels. This decreases their muscle tone and causes vasodilation.

Phosphodiesterase inhibitors

  • Sildenafil (Viagra®)
  • Tadalafil (Cialis®)
  • Cilostazol

Indications

Sildenafil and tadalafil treats erectile dysfunction. Can also be used to treat pulmonary hypertension. Unlike alprostadil, sildenafil only induces erection in the context of sexual stimulation.

Cilostazol are used to treat intermittent claudication.

Mechanism of action

Sildenafil inhibits phosphodiesterase type 5 (PDE5). This isoform of PDE is found in the corpus cavernosum (and the pulmonary circulation).

When sexual stimulation the brain signals the corpus cavernosum to release NO. This activates guanylate cyclase, which forms cGMP which causes muscle relaxation in the corpus cavernosum, allowing blood to enter. These drugs inhibit PDE5 and therefore inhibit the degradation of cGMP, causing a stronger and longer-lasting erection.

Cilostazol inhibit phosphodiesterase in RBCs, causing an increase in cAMP levels. This increases the deformity of the RBC membrane.

Side effects

Hypotension with reflex tachycardia, headache, dizziness, flush. Sildenafil causes visual disturbances.

Alprostadil

Indications

Peripheral artery disease, erectile dysfunction.

Mechanism of action

Alprostadil is a synthetic prostaglandin E1 (PGE1). It increases the deformability of RBCs, inhibit platelet aggregation and enhances fibrinolysis. These changes enhance the microcirculation.

Dosing

For erectile dysfunction it is injected into the penis. For peripheral artery disease it is given IV.

Side effects

Hypotension, tachycardia.

Iloprost

Indications

Severe peripheral artery disease with risk for gangrene or amputation.

Mechanism of action

It is a synthetic prostacyclin I2 (PGI2). It induces vasodilation and inhibits platelet aggregation.

Cinnarizine and flunarizine

Indications

For peripheral vasospastic diseases like Raynaud’s phenomenon, Meniere syndrome, motion sickness and migraine prophylaxis.

Mechanism of action

These drugs are both calcium channel blockers and antihistamines.

Adrenergic alpha antagonists

  • Phentolamine
  • Prazosin

Indications

Raynaud’s phenomenon.

Mechanism of action

These drugs block the alpha receptor-mediated vasoconstriction.

Introduction to obesity

Main article: Obesity

Obesity is a complex, chronic disease, which increases the risk of many other disorders. The old mantra was that obesity should be managed with lifestyle changes, and that medical therapy was a last-line option. Nowadays, the scientific community is shifting more towards a practice where obesity is treated in the same manner as another very common chronic disease, hypertension. Hypertension can also be managed with lifestyle therapy alone but most patients with hypertension also require medical therapy.

Treating obesity significantly decreases morbidity and mortality, and we should use those tools which we have available, especially with the introduction of newer, more efficacious anti-obesity drugs (GLP-1 analogues).

Patient compliance should be high and there should be no contraindications before drug therapy is initiated. The weight lost by these drugs is usually regained if they're stopped. As such, lifelong treatment is often necessary.

Contraindications

Pregnancy or lactation. Unstable heart disease. Severe hypertension. Psychiatric disorders.

GLP-1 analogues

GLP-1 analogues were initially used as antidiabetics, but they've recently been used for weight loss as well, with high efficacy. These are administered as s.c. injections.

Compounds

  • Liraglutide (Saxenda®) - average weight reduction of 5%
  • Semaglutide (Wegovy®) - average weight reduction of 12%
  • Tirzepatide - average weight reduction of 16%

Mechanism of action

These drugs are GLP-1 derivatives. They stimulate insulin release, inhibit glucagon release and slow gastric emptying. These effects decrease the blood sugar and therefore decrease the risk for all diabetes-associated complications. Tirzepatide is also a glucose-dependent insulinotroptic polypeptide (GIP) analogue.

Side effects

Nausea, vomiting, constipation.

Bupropion-naltrexone

Buproption-naltrexone (Mysimba®) gives an average weight reduction of 5%.

Mechanism of action

Bupropion is an antidepressant and smoking cessation drug. Naltrexone is an opioid receptor antagonist used to treat opioid dependence. Combined they have an appetite-suppressing effect.

Side effects

Nausea, constipation, headache. It may affect the mood and increase the risk for suicide.

Orlistat

Orlistat is rarely used, due to severe side effects and limited efficacy. It gives an average weight reduction of only 2-3%.

Mechanism of action

Orlistat is a pancreatic lipase inhibitor. By inhibiting this enzyme, the absorption of ingested fat can be decreased. Up to 1/3 of ingested fats can be blocked from absorption. It also decreases LDL cholesterol levels and decreases HbA1c in diabetics.

Side effects

Orlistat causes severe steatorrhoea. Fat soluble vitamin deficiency. These side-effects can be reduced by reducing fat intake.

Dosage

3 times daily, with meals (obviously).

Interactions

Increases effects of coumarins due to decreased absorption of vitamin K.

Other drugs for obesity

Lorcaserin

Lorcaserin is not available for use in the EU and for that reason is probably not that important. It was approved in the US but the approval was withdrawn in 2020 due to studies showing it causing an increased risk of cancer. It's a 5-HT2C receptor agonist, which suppresses the appetite.

Phentermine, benzphetamine

These drugs should not be used more than 12 weeks in a row to prevent dependence. They are indirect sympathomimetics. They are structurally related to amphetamines and have amphetamine-like suppressing effects on the appetite.

Non-pharmacological treatments for obesity

Decreasing the size of the lumen of the stomach causes the patient to feel full earlier and therefore consume less food. Several surgical treatments can be used to do this.

Intra-gastric balloon: A balloon can be inserted into the stomach endoscopically and inflated. The balloon takes up space in the stomach. This is not a long-term solution.

Bariatric surgery: This term refers to many surgical treatments aimed at decreasing the size of the stomach. The most common is the gastric bypass, where part of the stomach is bypassed and the food enters the small intestine directly.